Abstract Alzheimer?s disease is the most common cause of dementia and fourth most common cause of death. Amyloid-beta (A?) plays a crucial role in initiation and progression of Alzheimer?s disease (AD). Accumulation of A? on the surface of neuronal cells is known to cause synaptic dysfunction and further cascade into other dysfunctions in AD. Removal of circulatory A? would shift the equilibrium of A? levels between brain and blood towards blood and thus would deplete brain amyloid levels and improve memory. Treatments that target and reduce A? accumulation may be beneficial to AD patients in terms of better living conditions. Recombinant Technologies [RTL] is working towards developing an extracorporeal apheresis device that would sequester blood A? in AD patients. RTL believes that safe and efficient removal of A? would offer benefit that other options may not achieve. The proposed device, namely, Amytrapper would help AD patients live better. The device is centered on our proprietary active pharmacological ingredient [API], a tetrameric retro-inverso peptide that is pegylated. The peptide has a high affinity for a specific motif on A? that is involved in misfolding and self- aggregation/oligomerization. Upon injection of the same API in the previous POC studies, we have demonstrated depletion from the brain of A?42 and cognition improvement in a clinically relevant mouse model of AD. In the preceding phase 1 research we have obtained proof of concept for this amytrapper device. We have successfully created and tested the amytrapper prototype column matrix which was composed of sepharose beads conjugated to pegylated RI-peptide. It bound and retained biotinylated A?42 (spiked) from a buffer solution or in presence of sera. Sera from mice, rat and humans and plasma from humans were spiked with A?42 were tested for binding by Amytrapper, in vitro. Amytrapper specifically and reproducibly bound biotinylated A?42 in the above experiments in a concentration dependent manner. The proposed phase 2 research is a logic extension of the successful phase 1 outcome. In this proposal, in addition to the Amy trapper column, we plan to introduce an added innovation in the form of an Amytrapper catheter [a medically viable catheter coated inside with the RI-PEG] and test them out in vitro and in vivo. Therefore, in Aim 1, we will generate and characterize large scale quantities Amytrapper sepharose beads. In Aim 2, Amytrapper-catheter will be generated and characterized in collaboration with a CRO who is specialized in catheters that are commercially available. In Aim 3, we plan to demonstrate in vivo target [A?] engagement by the API in a mouse model challenged with A? injections directly into the brain using a push-pull microdialysis apparatus. In Aim 4, we will study efficacy of the two Amytrapper devices in a rat model of Alzheimer?s Disease. Evaluations will include biochemical, immuno-histological, and behavioral parameters. We expect that the catheter would provide advantages such as ease of use and storage just like a saline drip. At the end of this study, we would have enough data to support the FDA approval of these new devices for eventual first in human [FIH] study. We present well defined goals with realistic milestones and deliverables together with a viable commercialization plan that is supported by established players and partners. We believe that treatments targeting A? may be beneficial to amyloid toxicity in AD patients and improve their living conditions. We also believe we can succeed in creating this device soon for human use.